Clear cell renal cell carcinoma: Gene expression analyses identify a potential signature for tumor aggressiveness
Clear cell renal cell carcinoma: Gene expression analyses identify a potential signature for tumor aggressiveness
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DOI：
10.1158/1078-0432.ccr-05-0073
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发表时间：
2005-07-15
影响因子：
11.5
通讯作者：
Vasmatzis, G
中科院分区：
文献类型：
--
作者：
Kosari, F;Parker, AS;Vasmatzis, G
目的：本研究的目的是使用基因表达谱来确定新的生物标志物，是预测在透明细胞肾细胞癌（CCRCC）的侵略行为实验设计：候选基因被发现使用人类基因组U133加2阵列和验证独立的样本通过定量逆转录-PCR（RT-PCR）。发现和验证队列包括非侵袭性原发性CCRCC，侵袭性原发性CCRCC，转移性CCRCC，和非肿瘤性肾邻近tumor.Results：侵袭性原发性和转移性CCRCC显示没有显着差异的基因表达。相反，我们发现非侵袭性和侵袭性CCRCC（包括转移性CCRCC）之间的基因表达存在显著差异。通过微阵列分析显示最显著差异表达的35个转录物中的34个在使用定量RT-PCR的独立验证研究中也显示显著差异表达（对于31个候选物P < 0.001，对于其余3个候选物P < 0.005）。使用我们的候选标记物对定量RT-PCR数据进行分层聚类，准确地将88%（23/26）的侵袭性和转移性CCRCC样本、100%（14/14）的非侵袭性CCRCC样本和100%（15/15）的非肿瘤性样本分成单独的聚类。最后，我们评估了我们的候选标志物之一（生存素）的蛋白表达水平预测1990年至1992年在马约诊所接受手术治疗的183例CCRCC患者的生存率的能力。在多变量分析中，生存素（BIRC 5）的表达与癌症特异性生存呈负相关（P = 0.017）。结论：我们使用了基因组分析和定量PCR验证相结合，以确定一组候选生物标志物CCRCC的侵袭性。我们的数据还表明，在原发性肿瘤中可以识别导致侵袭行为和转移潜力的基因表达改变。
Purpose: The objective of this study was to use gene expression profiling to identify novel biomarkers that are predictive of aggressive behavior in clear cell renal cell carcinoma (CCRCC).Experimental Design: Candidate genes were discovered using Human Genome U133 Plus 2 Arrays and validated on independent samples by quantitative reverse transcription-PCR (RT-PCR). Both the discovery and the validation cohorts included nonaggressive primary CCRCC, aggressive primary CCRCC, metastatic CCRCC, and nonneoplastic kidney adjacent to tumor.Results: Aggressive primary and metastatic CCRCC displayed no significant differences in gene expression. In contrast, we identified significant differences in gene expression between nonaggressive and aggressive CCRCC (including metastatic CCRCC). Thirty-four of the 35 transcripts that displayed the most significant differential expression by microarray analysis also displayed significant differential expression in independent validation studies using quantitative RT-PCR (P < 0.001 for 31 candidates and P < 0.005 for the remaining three candidates). Hierarchical clustering of the quantitative RT-PCR data using our candidate markers accurately grouped 88% (23 of 26) of aggressive and metastatic CCRCC samples, 100% (14 of 14) of nonaggressive CCRCC samples, and 100% (15 of 15) of nonneoplastic samples into separate clusters. Finally, we evaluated the ability of protein expression levels of one of our candidate markers (survivin) to predict survival among a cohort of 183 CCRCC patients treated surgically at Mayo Clinic from 1990 to 1992. In multivariate analysis, expression of survivin (BIRC5) was inversely associated with cancer-specific survival (P = 0.017).Conclusion: We used a combination of genomic profiling and validation by quantitative PCR to identify a panel of candidate biomarkers for determining CCRCC aggressiveness. Our data also indicate that the gene expression alterations that result in aggressive behavior and metastatic potential can be identified in the primary tumor.